Imidazolidinedione derivatives and use thereof as drugs

ABSTRACT

The present invention is to provide an imidazolidinedione derivative and oxazolidinedione derivative represented by the following general Formula (I) having the chymase and/or tryptase inhibition activity 
                 
 
[wherein R 1  and R 2  are the same or different, and denote a lower alkyl group or a phenyl group, or R 1  and R 2  are taken together to form a ring, R 3  denotes an optionally substituted naphthyl group or heterocyclic group, A denotes oxygen or NR 4  (R 4  is hydrogen or optionally substituted lower alkyl group), or NB 2 R 5  (R 5  is aryl group, and B 2  is carbonyl group or sulfonyl group), and B 1  denotes a carbonyl group or a sulfonyl group], or a pharmaceutically acceptable salt thereof.

This application is a U.S. national stage of International ApplicationNo. PCT/JP02/03509 filed Apr. 8, 2002.

TECHNICAL FIELD

The present invention relates to an imidazolidinedione derivative oroxazolidinedione derivative or a pharmaceutically acceptable saltthereof, and a medicament containing these. These compounds have thechymase and/or tryptase inhibition activity, and are useful forpreventing or treating various diseases associated with chymase and/ortryptase.

BACKGROUND ART

Chymase is one of neutral serine proteases (about 30 kD), and since itis an enzyme which converts angiotensin I into angiotensin II in tissues[J. Biol. Chem., vol.265, pp.22348 (1990)], it is said to be associatedwith induction of cardiac or circulatory diseases caused by angiotensinII. In addition, since chymase has been revealed to have the activity ofpromoting activation from collagenase to active collagenase, limitativedegradation of extracellular matrix, thrombin or IgG, and release ofhistamine from mast cells, it is thought that chymase is also involvedin allergic or inflammatory diseases. Further, although the action ofchymase in the ocular tissue has not been completely elucidated, it isthought to be involved in regulating ophthalmic circulation (ophthalmicblood stream, aqueous humor circulation) and ciliary muscle. From theaforementioned wide activities of chymase in a living body, it isexpected that an agent which inhibits such the enzyme is useful as anagent for preventing and treating various diseases.

As a chymase inhibiting agent, there have been previously known animidazolidine derivative [(WO 96/04248 (counterparts: EP721944, U.S.Pat. No. 5,691,335)], an acetamide derivative [WO 98/09949 (counterpart:EP936216)], a triazinesulfone derivative (JP-H10-245384 A), athiazolidine derivative (JP-2000-95770 A, JP-2000-103785 A), aquinazoline derivative (WO 97/11941), a phenolester derivative(JP-H10-87567A), a thiazine derivative (EP 0713876), a heterocyclicamide compound [WO 96/33974 (counterpart: EP826671, U.S. Pat. No.5,948,785), WO 98/18794 (counterpart: EP940400, U.S. Pat. No.6,080,738)], a peptide compound [Proc. Natl. Acad. Sci. U.S.A., vol.92,pp6738 (1995)], a hydantoin derivative (JP-H09-31061A), and so on.However, these compounds have not been put into practice yet.

Tryptase, like chymase, belongs to a serine protease family, and isisolated and purified from human lung as a protease having thetrypsin-like substrate specificity [J. Biol. Chem, vol. 259, pp11046,(1984)]. Tryptase is present mainly in mast cells, and is also presentin lymphocyte and bronchial mucous secreting cells, and is characterizedin that, even after released to outside cells, the activity issufficiently maintained in plasma or extracellular space. In mast cells,a majority of tryptase is stored in secretory granules and, when cellsare activated, tryptase together with other enzymes (peroxidase, chymaseetc.) and chemical mediators (e.g. histamine. leukotrienes,prostaglandins) is released by degranulation [N. Engl. J. Med., vol.316, pp1622 (1987)].

Tryptase is related to a variety of diseases. For example, sincetryptase increases the contractility of airway smooth muscle byinactivating a vasoactive intestinal peptide having the broncodilatoryactivity, it is said to be one cause for asthma [J. Pharmacol. Exp.Ther., vol. 244, pp133 (1988)]. In addition, tryptase has been shown topromote cell proliferation of fibroblast, and is said to be involved ininterstitial pneumonia, pulmonary fibrosis, hepatic fibrosis, hepaticcirrhosis and pterygium [J. Clin. Invest., vol. 88, pp493 (1991), J JpnOphthalmol Soc, vol. 101, pp662 (1997)]. In addition, since tryptaseactivates prostoromelisin to cause activation of collagenase, andinitiate destruction of cartilage and periodontal connecting tissue,tryptase may be a cause for arthritis or periodontal disease, and may beinvolved in other various tissue inflammations and re-building. Further,since tryptase cleaves a calcitonin gene-related peptides, it isinvolved in neurogenic inflammation [Am. J. Respir. Cell Mol. Biol.,vol. 4, pp387 (1991)]. Tryptase promotes blood coagulation disorder byinactivating the coagulation precursor function of high-molecularkininogen, and degrading fibrinogen. Viruses having an outer membraneglycoprotein such as influenza and Sendai viruses are fused with atarget cell membrane by degradation of the glycoprotein by tryptase andinvade the cells. Examples of the virus include parainfluenza viruses,RS viruses, measles viruses and mumps viruses. As a tryptase inhibitingagent, natural leupeptin and antipain and some benzamidine derivativesare known [Biol. Chem. Hoppe-Seyler, vol.369, pp617 (1988)]. Besides,there are known an aminohexanoyl derivative (JP 2000-302675A), apolyfluoroalkylated tripeptide derivative [JP-H05-112598 A(counterparts: EP503203, U.S. Pat. Nos. 5,391,705, 5,498,779,5,563,156)], a peptide derivative [JP-H08-507768 A (counterpart:EP688337)], a secretory leukocyte protease inhibitor (JP-10-505833 A), aleech-derived polypeptide [JP-H09-500532 A (counterparts: EP714408, U.S.Pat. No. 5,972,698)], a guanidine derivative (JP-Re 97/037969 A),antileukoprotease (JP-Re 95/025539 A), associated peptides (JPRe97/003694-A), and so on. However, these compounds have not been putinto practice yet.

OBJECT OF THE INVENTION

An object of the present invention is to provide a novelimidazolidinedione derivative and oxazolidinedione derivative having theexcellent chymase and/or tryptase inhibiting activity.

DISCLOSURE OF THE INVENTION

The present inventors studied intensively and, as a result, generated animidazolinedione derivative and an oxazolidinedione derivative havingthe excellent chymase and/or tryptase inhibition activity, and furtherresearched, which resulted in completion of the present invention.

That is, the present invention relates to:

(1) a compound represented by the general formula (I):

[wherein R¹ and R² are the same or different, and denote a lower alkylgroup or a phenyl group, or R¹ and R² are taken together to form a ring,R³ denotes an optionally substituted naphthyl group or heterocyclicgroup, A denotes oxygen or NR⁴ (R⁴ is hydrogen or optionally substitutedlower alkyl group), or NB²R⁵ (R⁵ is aryl group, and B² is carbonyl groupor sulfonyl group), and B¹ denotes a carbonyl group or a sulfonylgroup], or a pharmaceutically acceptable salt thereof,

(2) the compound according to the (1), wherein R¹ and R² are the same ordifferent, and are a lower alkyl group or a phenyl group, R³ is a furylgroup or an optionally substituted naphthyl group, and A is oxygen orNR⁴ (R⁴ is hydrogen or optionally substituted lower alkyl group) in thegeneral formula (I), or a pharmaceutically acceptable salt thereof,

(3) the compound according to the (1), wherein B¹ and B² are a carbonylgroup in the general formula (I), or a pharmaceutically acceptable saltthereof,

(4) a medicament, which comprises the compound described in any one ofthe (1) to (3), or a pharmaceutically acceptable salt thereof,

(5) a chymase and/or tryptase inhibiting agent, which comprises thecompound described in any one of the (1) to (3), or a pharmaceuticallyacceptable salt thereof,

(6) the medicament described in the (4), which is an agent forpreventing or treating diseases associated with chymase and/or tryptase,

(7) the medicament described in the (6), wherein the disease associatedwith chymase and/or tryptase is allergic, inflammatory or circulatorydisease,

(8) the medicament described in the (6), wherein the disease associatedwith chymase is chorioretinopathy, glaucoma, myopia or asthenopia,

(9) a pharmaceutical composition, which comprises the compound describedin any one of the (1) to (3), or a pharmaceutically acceptable saltthereof,

(10) a method of preventing or treating diseases associated with chymaseand/or tryptase, which comprises administering an effective amount ofthe compound described in any one of the (1) to (3), or apharmaceutically acceptable salt thereof to a warm-blooded animal,

(11) a use of the compound described in any one of (1) to (3), orpharmaceutically acceptable salt thereof for manufacturing a chymaseand/or tryptase inhibiting agent.

DETAILED DESCRIPTION OF THE INVENTION

In the compound represented by the general formula (I) of the presentinvention, a lower alkyl group represented by R¹ and R² refers to astraight or branched alkyl group having a carbon number of 1 to 5, suchas a methyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, anisopentyl group, a neopentyl group and a tert-pentyl group, particularlypreferably a methyl group.

In addition, examples of a ring which R¹ and R² may be taken together toform include a ring having a carbon number of 3 to 7, such ascyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane.Preferably, the ring is cyclohexane.

A heterocyclic group represented by R³ is a 5-membered or 6-memberedcompound containing at least one of an oxygen atom, a sulfur atom and anitrogen atom, such as a furyl group, a thienyl group, a pyrrolyl groupand a pyridyl group, preferably a furyl group. In addition, a naphthylgroup and a heterocyclic group represented by R³ may have a substituentsuch as a carboxyl group.

A lower alkyl group of R⁴ represented by NR⁴ in A has the same meaningas that of a lower alkyl group represented by R¹ and R², and examples ofa substituent include a phenyl group and a benzoyl group which may havea substituent, and a carboxyl group optionally esterified with a loweralkyl group. Examples of a substituent of a phenyl group include ahalogen (e.g. chlorine, fluorine, bromine etc.), a cyano group, and soon. Examples of a substituent of a benzoyl group include lower alkylgroups having a carbon number of 1 to 3 (methyl group, ethyl group,propyl group, isopropyl group) and lower alkoxy groups (methoxy group,ethoxy group, propoxy group, isopropoxy group). As a lower alkyl group,a methyl group is preferable. As a lower alkoxyl group, a methoxy groupis preferable.

Examples of an aryl group of R⁵ represented by NB²R⁵ in A include aphenyl group, a naphthyl group and a 2-naphthyl group, preferably anaphthyl group and a 2-naphthyl group. As a carbonyl group and asulfonyl group represented by B¹ and B², a carbonyl group is morepreferable.

The compound represented by the general formula (I) of the presentinvention can be prepared by the following preparing method, or by asimilar method.

i) Case where A is oxygen:

[wherein R¹, R², R³ and B¹ are as defined above, and X denotes halogenatom (chlorine, bromine, fluorine, iodine etc.)]

A compound of the general formula (I′) in which A in the compoundrepresented by the general formula (I) is oxygen, can be prepared byreacting 5,5-di-substituted oxazolidin-2,4-dione represented by theformula (II) or a salt thereof with an acid halide derivativerepresented by the formula (III), and performing the conventionalpurification such as recrystallization, column chromatography and thelike.

Such the reaction can be carried out in a reaction solvent in thepresence or absence of an inorganic base or an organic base. Examples ofa reaction solvent which can be used in the present reaction include theconventional solvents which do not have adverse influence on a reaction,such as methylene chloride, chloroform, N,N-dimethylformamide, benzene,toluene, ethylbenzene, cyclohexane, hexane, heptane, diethyl ether,tetrahydrofuran and the like, and a mixed solvent thereof, preferablyN,N-dimethylformamide and tetrahydrofuran.

An inorganic base used in the present reaction include alkali metalhydrides such as sodium hydride and the like, alkali metal carbonatessuch as potassium carbonate, and alkali metal bicarbonates such assodium bicarbonate. Examples of an organic base include trialkylaminesuch as triethylamine, diisopropylethylamine and the like, pyridine,lutidine, picoline, 4-dimethylaminopyridine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and the like. Sodium hydride andpotassium carbonate are preferable. Such the base is preferably used ina range of 0.1 to 2.0 molar ratio relative to 1 mol of5,5-di-substituted oxazolidine-2,4-dione represented by the formula (II)or a salt thereof. A reaction temperature is usually in a range of undercooling to under warming, preferably in a range of −10° C. to 30° C.

ii) Case where A is NR⁴ or NB²R⁵:

[wherein respective symbols are as defined above]

A compound of the formula (V) in which A in the compound represented bythe general formula (I) is NR⁴(R⁴ is hydrogen), can be prepared byreacting 5,5-di-substituted imidazolidine-2,4-dione represented by theformula (IV) or a salt thereof with an acid halide derivativerepresented by the formula (III) under the same conditions as those forthe i), and performing the conventional purification such asrecrystallization, column chromatography and the like. Further, acompound of the formula (I″) or (I′″) in which A in the compoundrepresented by the general formula (I) is denoted by NR⁴ or NB²R⁵, canbe prepared by reacting with an alkyl halide derivative (VI) or an acidhalide derivative(VII), and performing the conventional purificationprocedure such as recrystallization, column chromatography and the like.The reaction can be carried out by using an alkyl halide derivative oran acid halide derivative in a range of a molar ratio of 0.5 to 2.0,preferably a molar ratio of 0.9 to 1.2 relative to the compoundrepresented by the formula (V) under the same other reaction conditionsas those for the i).

When the acid halide derivative (VII) and the compound represented bythe formula (III) are the same, the compound of the formula (I′″) can beeasily obtained by performing a reaction by adding the compoundrepresented by the formula (III) at a molar ratio of 2 to 2.2 relativeto 1 mol of the compound represented by the formula (IV).

Examples of preferable compounds of the present invention are asfollows:

-   (1) 3-(2-Naphthylcarbonyl)-5,5-diphenylimidazolidine-2,4-dione,-   (2) 3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione,-   (3) Ethyl    2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate,-   (4) tert-Butyl    2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate,-   (5) 3-Naphtylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinylacetic    acid,-   (6)    4-((2,5-Dioxo-4,4-diphenylimidazolidinyl)carbonyl)naphthalenecarboxylic    acid,-   (7) 5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione,-   (8) 5,5-Dimethyl-3-naphthylcarbonyl imidazolidine-2,4-dione,-   (9) 5,5-Dimethyl-3-naphthylcarbonyl-1,3-oxazolidine-2,4-dione,-   (10) 3-(2-Furylcarbonyl)-5,5-diphenylimidazolidine-2,4-dione,-   (11) 3-(2-Naphthylsulfonyl)-5,5-diphenylimidazolidine-2,4-dione,-   (12) 3-Naphthylsulfonyl-5,5-diphenylimidazolidine-2,4-dione,-   (13) tert-Butyl    (5,5-dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinyl)acetate,-   (14) tert-Butyl    (5-methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinyl)acetate,-   (15) 5,5-Dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinylacetic    acid,-   (16)    5-Methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinylacetic    acid,-   (17) 5,5-Dimethyl-3-(2-naphthylsulfonyl)imidazolidine-2,4-dione,-   (18) 5,5-Dimethyl-3-naphthylsulfonylimidazolidine-2,4-dione,-   (19)    5-Methyl-3-(2-naphthylsulfonyl)-5-phenylimidazolidine-2,4-dione,-   (20)    1-Benzyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione,-   (21)    3-Naphthylcarbonyl-1-(2-oxo-2-phenylethyl)-5,5-diphenylimidazolidine-2,4-dione,-   (22)    1-Methyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione,-   (23)    1-Isobutyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione,-   (24)    1-(4-Fluorobenzyl)-5-methyl-3-naphthylcarobnyl-5-phenylimidazolidine-2,4-dione,-   (25)    1-(3-Chlorobenzyl)-5-methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione,-   (26)    5-Methyl-3-naphthylcarbonyl-1-(2-oxo-2-phenylethyl)-5-phenylimidazolidine-2,4-dione-   (27)    4-(5,5-Dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinylmethyl)benzonitrile,-   (28)    1-(3-Chlorobenzyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione,-   (29)    1-(4-Chlorobenzyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione,-   (30)    5,5-Dimethyl-3-naphthylcarbonyl-1-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione,-   (31)    5,5-Dimethyl-3-naphthylcarbonyl-1-(2-oxo-2-p-tolylethyl)imidazolidine-2,4-dione,-   (32)    1-(2-(4-Methoxyphenyl)-2-oxoethyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione,-   (33) 5,5-Dimethyl-1,3-bisnaphthylcarbonylimidazolidine-2,4-dione,-   (34) 3-Naphthylcarbonyl-1,3-diazaspiro[4,5]decane-2,4-dione,-   (35)    5,5-Dimethyl-1,3-bis-(2-naphthylsulfonyl)imidazolidine-2,4-dione,-   (36) 5,5-Dimethyl-1,3-bisnaphthylsulfonylimidazolidine-2,4-dione,-   (37)    5-Methyl-1,3-bis-(2-naphthylsulfonyl)-5-phenylimidazolidine-2,4-dione.

Examples of a pharmaceutically acceptable salt of the compoundrepresented by general formula (I) of the present invention includealkali metal salts such as a sodium salt and a potassium salt, alkalineearth metal salts such as a calcium salt and a magnesium salt, saltswith inorganic acids such as hydrochloride, hydrobromide, sulfate,nitrate and phosphate, and salts with organic acids such as acetate,citrate, and toluenesulfonate, being not limiting.

In addition, the present invention includes various solvates and crystalpolymorphisms of the compound represented by the general formula (I),and prodrugs thereof

The compound represented by the general formula (I) of the presentinvention and a pharmaceutically acceptable salt thereof (hereinafter,referred to as the present compound in some cases) are novel compoundswhich have not described in literatures yet and, since they have theexcellent chymase and/or tryptase inhibition activity as shown inExperimental Example described later, they are useful as a medicament asa chymase and/or tryptase inhibiting agent containing them as an activeingredient by combining with a carrier described later as necessary.

Since the present compound has the chymase and/or tryptase inhibitionactivity, the compound is useful for preventing or treating diseasesassociated with chymase and/or tryptase, of a warm-blooded animal(mammals such as human, monkey, dog, cat, rabbit, guinea pig, rat,hamster and mouse, birds such as chicken, pigeon, turkey).

For example, by the chymase and tryptase inhibition activity, thepresent compound can be used as an agent for preventing or treatingsystemic or local inflammatory or allergic diseases (e.g. digestivetract inflammatories such as pancreatitis, ulcerative colitis andCrohn's disease, and nephritis, hepatitis, bronchopneumonia, atopy,arthritis and rheumatism as systemic disease, keratoconjunctivitis,iridocyclitis, uveitis, orbital inflammation, vernal catarrh, allergicrhinitis), or as an agent for preventing or treating restenosis aftercirculatory diseases (eg. hypertension, arterial sclerosis, cardiacinfarct, hypercardia, heart failure), restenosis after blood vesseldisorder due to percutaneous transluminal angioplasty, diabetic andnon-diabetic renal disorder, and peripheral circulatory disorder, or asan agent for preventing or treating itching associated with inflammatoryor allergic disorders. By the chymase inhibition activity, the presentcompound can be used as an agent for preventing or treating ophthalmiccirculatory damaging diseases (chorioretinopathy; retinitis pigmentosa,macular degeneration, ischemic optic nerve disease, arteriovenousocculusion, diabetic retinopathy, choroidal disease following retinallesion) and glaucoma. In addition, since the present compound hasciliary muscle relaxing activity of contracting, it can be used forimproving myopia or asthenopia. In addition, by the tryptase inhibitionactivity, the present compound can be used as an agent for preventing ortreating blood coagulation disorder such as thrombophlebitis anddisseminated intravascular coagulation, psoriasis, dermal diseases suchas scleroderma and virus diseases, as well as interstitial pneumonia,pulmonary fibrosis, hepatic cirrhosis, periodontal diseases andpterygium.

For the aforementioned prevention and treatment, the present compoundcan be appropriately applied orally or parenterally. Examples of theform of the preparation include solid preparations such as tablets,granules, powders, capsules, ointments and the like and liquidpreparations such as injectables, eye drops, nasal drops and the like.Any preparations can be appropriately prepared by the known method. Inthese preparations, normally used excipients (starch, glucose, fructose,sucrose, calcium phosphate etc.), binders (starch, gum arabic, gelatinsolution, sodium arginate, carmerose solution etc.), disintegratingagents (starch, potassium carbonate, crystalline cellulose etc.),lubricants (stearic acid, magnesium stearate, talc etc.), absorptionpromoters (thioglycolic acid, capric acid, caprylic acid etc.), buffers(boric acid, borax, sodium acetate, citrate buffer, phosphate bufferetc.), surfactants (sodium laurylsulfate, Polysorbate 80,polyoxyethylene hydrogenated castor oil etc.), solubilizers (sodiumlaurylsulfate, sodium benzoate, ethylenediamine, potassium iodide etc.),preservatives (benzalkonium chloride, parabens, chlorobutanol etc.),emulsifiers (gum arabic, tragacanth, gelatin, polyvinylpyrrolidoneetc.), isotonics (sodium chloride, glycerin, mannitol etc.), stabilizers(sodium edetate, sodium pyrosulfite etc.), pH adjusting agents(hydrochloric acid, citric acid, sodium hydroxide etc.) and the like maybe appropriately used.

When the present compound is used, for example, as an agent forpreventing or treating circulatory diseases, a dose varies depending ona kind of a subject disease, a kind of a compound to be used, an age, aweight and symptom of a patient and its dosage form and, for example inthe case of an internal preparation, the present compound may beadministered to an adult patient a few times per day at a one timeamount of 1 mg to 100 mg, more preferably 5 mg to 25 mg. In addition, inthe case of an intravenous injectable, the present compound may beadministered to the same patient once per day at 0.1 mg to 25 mg, morepreferably 0.5 to 5 mg. Further, when locally administered to a patientwith local inflammatory disease, an eye drops, a nasal drop or anointment containing the present compound at 0.01 w/v % to 2.0 w/v %,preferably 0.05 w/v % to 0.5 w/v % is dropped to eyes, dropped to nosesor coated at 1 to a few drops or an appropriate amount per once, once to8 times per day.

The present compound may be used by appropriately combining two or morekinds depending on the purpose and the necessity. In addition, as far asit is not contrary to the object of the present invention, the presentcompound may be used by appropriately combining with chymase and/ortryptase inhibiting ingredients which are not included in the presentinvention, other ingredients having the same drug efficacy as that ofthe present invention, and other effective ingredients.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be explained in more detail by the followingExamples and Experimental Examples, but the present invention is notlimited by them at all.

In physical property values of the compounds described in Examples,nuclear magnetic resonance spectrum (NMR) was measured using VarianGemini 2000.

EXAMPLE 1 3-(2-Naphthylcarbonyl)-5,5-diphenylimidazolidine-2,4-dione(Compound 1)

0.5 g of 5,5-diphenylimidazolidine-2,4-dione was dissolved intetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,2-naphthoyl chloride (415 mg) was added at 0° C., followed by stirringat room temperature for 2.5 hours. After water was carefully added,ethyl acetate (200 mL) was added, and the layers were separated. Theresulting organic layer was washed with a saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was distilled off.Further purification by silica gel chromatography (hexane:ethylacetate=3:1) afforded white crystals. The resulting fraction wasrecrystallized from isopropyl ether (IPE) to obtain 441 mg of whitecrystals.

¹H-NMR (CDCl₃) δ7.25 (1H, brs), 7.38-7.48 (10H, m), 7.54 (1H, ddd,J=8.1, 6.9, 1.2 Hz), 7.63 (1H, ddd, J=8.3, 6.9, 1.4 Hz), 7.79-7.89 (4H,m), 8.26 (1H, d, J=1.2 Hz).

¹³C-NMR (CDCl₃) δ70.6, 125.0, 126.9, 127.1, 127.9, 128.7, 129.0, 129.1,129.4, 129.8, 132.2, 133.0, 136.3, 138.4, 153.4, 165.9, 171.0.

EXAMPLE 2 3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione(Compound 2)

0.5 g of 5,5-diphenylimidazolidine-2,4-dione was dissolved intetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,1-naphthoyl chloride (396 mg) was added at 0° C., followed by stirringat room temperature for 2.5 hours. After water was added carefully,ethyl acetate (200 mL) was added, and the layers were separated. Theresulting organic layer was washed with a saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was distilled off.Further purification by silica gel chromatography (hexane: ethylacetate=7:3) afforded 544 mg of white powder.

¹H-NMR (CDCl₃) δ6.95 (1H, brs), 7.36-7.42 (9H, m), 7.43 (1H, d, J=7.3Hz), 7.46 (1H, d, J=7.2 Hz), 7.52-7.61 (2H, m), 7.71 (1H, dd, J=7.3, 1.2Hz), 7.89-7.92 (1H, m), 8.06 (1H, d, J=8.2 Hz), 8.45-8.48 (1H, m).

¹³C-NMR (CDCl₃) δ70.2, 124.4, 124.7, 126.9, 128.6, 128.8, 129.0, 129.0,129.6, 130.2, 130.8, 133.7, 134.5, 138.4, 152.9, 165.8, 171.2.

EXAMPLE 3 Ethyl2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate(Compound 3)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (406 mg) wasdissolved in dimethylformamide (DMF: 2 mL), ethyl bromoacetate (167 mg)was added, and potassium carbonate (138 mg) was further added. Thereaction solution was stirred at room temperature overnight. After waterwas added carefully, ethyl acetate (100 mL) was added, followed byextraction. The resulting organic layer was washed with a saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Recrystallization from methanol afforded 338 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.03 (3H, t, J=7.1 Hz), 3.79 (2H, q, J=7.1 Hz), 4.13(2H, s), 7.26-7.62 (13H, m), 7.78 (1H, dd, J=7.1, 1.3 Hz), 7.89-7.92(1H, m), 8.07 (1H, d, J=8.4 Hz), 8.46-8.49 (1H, m).

¹³C-NMR (CDCl₃) δ13.9, 42.6, 61.5, 74.8, 124.4, 124.8, 126.8, 128.5,128.8, 129.0, 129.4, 129.7, 130.1, 130.8, 133.7, 134.4, 136.2, 152.6,165.7, 166.6, 170.7.

EXAMPLE 4 tert-Butyl2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate(Compound 4)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (879 mg) wasdissolved in DMF (3 mL), tert-butyl bromoacetate (421 mg) was added, andpotassium carbonate (299 mg) was further added. The reaction solutionwas stirred at room temperature overnight. After water was carefullyadded, ethyl acetate (200 mL) was added, followed by extraction. Theresulting organic layer was washed with a saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was distilled off.Further, recrystallization from methanol afforded 846 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.17 (9H, s), 4.05 (2H, s), 7.33-7.61 (13H, m), 7.78(1H, dd, J=7.3, 1.2 Hz), 7.90 (1H, d, J=7.3, 2.3 Hz), 8.06 (1H, d, J=8.4Hz), 8.45-8.48 (1H, m).

¹³C-NMR (CDCl₃) δ27.7, 43.2, 74.8, 82.2, 124.4, 124.8, 126.8, 128.5,128.6, 128.7, 128.9, 129.3, 129.8, 130.1, 130.8, 133.7, 134.3, 136.4,152.5, 165.3, 165.7, 170.8.

EXAMPLE 5 3-Naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinylaceticacid (Compound 5)

tert-Butyl2-(3-naphthylcarbonyl-2,4-dioxo-5,5-diphenylimidazolidinyl)acetate (300mg) was dissolved in a 20% trifluoroacetic acid/dichloromethane solution(2 mL), and the solution was stirred at room temperature overnight.After a 1N aqueous hydrogen chloride solution was added, the solutionwas extracted three times using chloroform (50 mL). The resultingorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was distilled off. Further,recrystallization from IPE afforded 231 mg of white crystals.

¹H-NMR (CDCl₃) δ4.11 (2H, s), 7.31-7.61 (13H, m), 7.74 (1H, dd, J=7.3,1.2 Hz), 7.89-7.92 (1H, m), 8.06 (1H, d, J=8.4 Hz), 8.44-8.47 (1H, m).

¹³C-NMR (CDCl₃) δ42.1, 74.9, 124.4, 124.7, 126.8, 128.4, 128.5, 128.8,129.0, 129.6, 130.2, 130.7, 133.7, 134.5, 135.9, 152.6, 165.6, 170.6,171.4.

EXAMPLE 64-((2,5-Dioxo-4,4-diphenylimidazolidinyl)carbonyl)naphthalenecarboxylicacid (Compound 6)

1,4-Naphthalenedicarboxylic acid (0.43 g) was dissolved in thionylchloride (1.89 g), and the solution was stirred at room temperature for3 hours. The solvent was distilled off under reduced pressure, and asuspension of a potassium salt (0.58 g) of5,5-diphenylimidazolidine-2,4-dione in tetrahydrofuran (5 mL) was addedto the residue. After stirred for 2 hours, water (20 mL) was added,ethyl acetate (200 mL) was further added, and the layers were separated.The resulting organic layer was washed with a saturated brine, and driedwith anhydrous magnesium sulfate, and the solvent was distilled offFurther silica gel chromatography with ethyl acetate afforded 244 mg ofthe pale yellow solid.

¹H-NMR (DMSO-d₆) δ7.34-7.48 (10H, m), 7.69 (1H, dd, J=3.4, 6.8 Hz),7.74-7.86 (1H, m), 8.07-8.15 (2H, m), 8.78 (1H, dd, J=3.4, 6.8 Hz), 9.30(1H, brs), 11.10 (1H, brs).

¹³C-NMR (DMSO-d₆) δ70.3, 125.9, 126.1, 126.6, 126.9, 127.6, 127.9,128.1, 128.2, 128.6, 128.9, 130.7, 132.3, 138.8, 139.9, 156.0, 168.5,174.9.

EXAMPLE 7 5-(Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione(Compound 7)

5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (228 mg) wassuspended in tetrahydrofuran (5 mL), 1-naphthoyl chloride (188 mg) wasadded, and the mixture was stirred at room temperature overnight. To thereaction solution was added ethyl acetate (20 mL), and the mixture wasfiltered with a membrane filter (0.25 μm). After the solvent wasdistilled off, 364 mg of the resulting organic layer was purified bysilica gel chromatography (hexane:ethyl acetate=2:1). Furtherrecrystallization from ethyl acetate/IPE afforded 134 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.86 (3H, s), 6.20 (1H, brs), 7.34-7.45 (5H, m),7.49-7.59 (5H, m), 7.65 (1H, dd, J=7.2, 1.2 Hz), 7.86-7.90 (1H, m), 8.04(1H, d, J=8.2 Hz), 8.40-8.44 (1H, m).

¹³C-NMR (CDCl₃) δ25.7, 63.7, 124.3, 124.6, 125.2, 126.8, 128.5, 128.7,128.8, 129.1, 129.6, 130.0, 130.7, 133.7, 134.4, 137.9, 153.1, 165.9,172.5.

EXAMPLE 8 5,5- Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione(Compound 8)

5,5-Dimethylimidazolidine-2,4-dione potassium salt (1.47 g) wassuspended in tetrahydrofuran (5 mL), 1-naphthoyl chloride (1.46 g) wasadded, and the mixture was stirred at room temperature overnight. Ethylacetate (50 mL) was added to the reaction solution, and the mixture wasfiltered with a membrane filter (0.25 μm). The resulting organic layerwas purified by silica gel chromatography (hexane:ethyl acetate=1:1) toobtain 674 mg of white crystals.

¹H-NMR (CDCl₃) δ1.43 (6H, s), 6.62 (1H, brs), 7.48-7.66 (3H, m), 7.74(1H, dd, J=7.3, 1.2 Hz), 7.92 (1H, d, J=7.8 Hz), 8.08 (1H, d, J=8.2 Hz),8.48 (1H, d, J=8.2 Hz).

¹³C-NMR (CDCl₃) δ25.2, 58.8, 124.4, 124.7, 126.8, 128.5, 128.8, 129.9,130.8, 133.8, 134.3, 152.8, 166.2, 174.6.

EXAMPLE 9 5,5-Dimethyl-3-naphthylcarbonyl-1,3-oxazolidine-2,4-dione(Compound 9)

5,5-Dimethyl-2,4-oxazolidinedione potassium salt (84 mg) was suspendedin tetrahydrofuran (1 mL), 1-naphthoyl chloride (95 mg) was added, andthe mixture was stirred at room temperature overnight. To the reactionsolution was added 4 mL of ethyl acetate, and the solution was filteredwith a membrane filter (0.25 μm). The resulting organic layer waspurified by silica gel chromatography (hexane:ethyl acetate=2:1), andfurther recrystallized from ethyl acetate/IPE to obtain 61 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.71 (6H, s), 7.52-7.71 (3H, m), 7.78 (1H, dd, J=7.3,1.2 Hz2 Hz), 7.95 (1H, dd, J=8.8, 1.5 Hz), 8.14 (1H, d, J=8.2 Hz2 Hz),8.57 (1H, dd, J=8.6, 1.0 Hz).

¹³C-NMR (CDCl₃) δ23.8, 83.6, 124.3, 124.6, 127.1, 128.1, 128.9, 129.1,130.8, 130.9, 133.9, 135.5, 150.4, 164.5, 173.3.

EXAMPLE 10 3-(2-Furylcarbonyl)-5,5-diphenylimidazolidine-2,4-dione(Compound 10)

5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved intetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes, 2-furoylchloride (235 mg) was added 0° C., and the mixture was stirred at roomtemperature for 2.5 hours. After water was added carefully, ethylacetate (200 mL) was added, and the layers were separated. The resultingorganic layer was washed with a saturated brine, and dried overanhydrous magnesium sulfate, and the solvent was distilled off. Furtherpurification by silica gel chromatography (hexane:ethyl acetate=2:1)afforded white powders. The resulting foam was recrystallized from IPEto obtain 273 mg of white crystals.

¹H-NMR (CDCl₃) δ6.59 (1H, dd, J=3.7, 1.7 Hz), 7.13 (1H, brs), 7.32 (1H,dd, J=3.7, 0.6 Hz), 7.37-7.45 (10H, m), 7.64 (1H, dd, J=1.7, 0.6 Hz).

¹³C-NMR (CDCl₃) δ70.6, 113.3, 123.1, 126.9, 128.9, 129.0, 138.4, 146.6,148.7, 152.8, 154.2, 170.5.

EXAMPLE 11 3-(2-Naphthylsulfonyl)-5,5-diphenylimidazolidine-2,4-dione(Compound 11)

5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved intetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,2-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and themixture was stirred at room temperature overnight. After water was addedcarefully, ethyl acetate (100 mL) was added, and the layers wereseparated. The resulting organic layer was washed with a saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=3:1 to 2:1) afforded 320 mg of white powder.

¹H-NMR (CDCl₃) δ6.70 (1H, brs), 7.17-7.34 (10H, m), 7.62-7.74 (2H, m),7.92-8.01 (3H, m), 8.05 (1H, dd, J=1.8, 8.6 Hz), 8.72 (1H, d, J=1.5 Hz).

¹³C-NMR (CDCl₃) δ70.2, 122.3, 126.8, 127.9, 128.0, 128.9, 129.0, 129.7,129.9, 130.0, 130.9, 131.8, 134.5, 135.9, 137.8, 150.7, 168.8.

EXAMPLE 12 3-Naphthylsulfonyl-5,5-diphenylimidazolidine-2,4-dione(Compound 12)

5,5-Diphenylimidazolidine-2,4-dione (0.5 g) was dissolved intetrahydrofuran (5 mL), and sodium hydride (60%, in oil) (87 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,1-naphthalenesulfonyl chloride (471 mg) was added at 0° C., and themixture was stirred at room temperature overnight. After water was addedcarefully, ethyl acetate (100 mL) was added, and the layers wereseparated. The resulting organic layer was washed with a saturatedbrine, and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. The material was dissolved in ethyl acetate, and purifiedby silica gel chromatography (hexane:ethyl acetate=3:1 to 2:1) to obtain100 mg of white powder.

¹H-NMR (CDCl₃+CD₃OD) δ7.13-7.37 (9H, m), 7.49-7.64 (4H, m), 7.95 (1H,m), 8.17 (1H, m), 8.53 (1H, m), 8.64 (1H, m).

¹³C-NMR (CDCl₃+CD₃OD) δ70.2, 123.3, 124.2, 127.0, 127.3, 128.5, 128.8,129.4, 129.7, 132.2, 133.1, 134.0, 136.6, 138.2, 151.1, 169.8.

EXAMPLE 13 Tert-butyl(5,5-dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinyl)acetate(Compound 13)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (686 mg) wasdissolved in DMF (5 mL), and tert-butyl bromoacetate (473 mg) was added.Potassium carbonate (352 mg) was further added, and the mixture wasstirred at room temperature overnight. After water was added carefullyto the reaction solution, ethyl acetate (200 mL) was added, followed byextraction. The resulting organic layer was washed with 1N hydrochloricacid, an aqueous saturated sodium bicarbonate solution and a saturatedbrine in turn, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off. Further purification by silica gelchromatography (hexane:ethyl acetate=2:1) afforded white crystals. Theresulting fraction was recrystallized from IPE to obtain 679 mg of whitepowders.

¹H-NMR (CDCl₃) δ1.48 (9H, s), 1.50 (6H, s), 3.93 (2H, s), 7.49-7.66 (3H,m), 7.78 (1H, dd, J=7.3, 1.2 Hz2 Hz), 7.91 (1H, dd, J=8.8, 1.5 Hz), 8.07(1H, d, J=8.2 Hz2 Hz), 8.50 (1H, d, J=8.9 Hz).

¹³C-NMR (CDCl₃) δ22.9, 23.1, 28.0, 41.5, 61.8, 124.3, 124.8, 126.7,128.5, 128.7, 129.8, 129.9, 130.8, 133.8, 134.3, 151.9, 165.9, 167.0,173.8.

EXAMPLE 14 tert-Butyl(5-methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinyl)acetate(Compound 14)

5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (800 mg) wasdissolved in DMF (8 mL) and tert-butyl bromoacetate (452 mg) was added.Potassium carbonate (336 mg) was further added, and the mixture wasstirred at room temperature overnight. After water was added carefullyto the reaction solution, ethyl acetate (200 mL) was added, followed byextraction. The resulting organic layer was washed with 1N hydrochloricacid, an aqueous saturated sodium bicarbonate solution and a saturatedbrine in turn, and dried over anhydrous magnesium sulfate, and thesolvent was distilled off. Further recrystallization with IPE afforded704 mg of white crystals.

¹H-NMR (CDCl₃) δ1.44 (9H, s), 1.96 (3H, s), 3.46 (1H, d, J=17.7 Hz),4.31 (1H, d, J=17.7 Hz), 7.38-7.63 (8H, m), 7.76 (1H, dd, J=7.3, 1.2 Hz2Hz), 7.90 (1H, dd, J=7.7, 1.7 Hz), 8.06(1H, d, J=8.2 Hz), 8.45-8.48 (1H,m).

¹³C-NMR (CDCl₃) δ21.1, 28.0, 42.7, 67.3, 82.7, 124.4, 124.8, 126.1,126.7, 128.5, 128.7, 129.3, 129.4, 130.0, 130.8, 133.7, 134.3, 134.4,136.1, 152.7, 165.8, 166.8, 171.8.

EXAMPLE 155,5-Dimethyl-3-(naphthylcarbonyl)-2,4-dioxoimidazolidinylacetic acid(Compound 15)

tert-Butyl (5,5-dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinyl)acetate (479 mg) was dissolved in a 20% trifluoroaceticacid/dichloromethane solution (10 mL), and the mixture was stirred atroom temperature overnight. After 0.5N hydrochloric acid was added, andthe solution was extracted twice using chloroform (100 mL). Theresulting organic layer was washed with a saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was distilled off.Further recrystallization from IPE afforded 396 mg of white crystals.

¹H-NMR (CDCl₃) δ1.47 (6H, s), 4.05 (2H, s), 7.48-7.65 (3H, m), 7.77 (1H,dd, J=8.3, 1.2 Hz), 7.90 (1H, d, J=7.6 Hz), 8.06 (1H, d, J=8.2 Hz), 8.48(1H, d, J=8.4 Hz).

¹³C-NMR (CDCl₃) δ25.0, 40.5, 62.0, 124.4, 124.7, 126.8, 128.6, 128.8,129.6, 130.1, 130.8, 133.7, 134.4, 152.3, 165.9, 171.8, 173.7.

EXAMPLE 165-Methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinylacetic acid(Compound 16)

Tert-butyl (5-methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinylacetate (400 mg) was dissolved in a 20% trifluoroaceticacid/dichloromethane solution (10 mL), and the mixture was stirred atroom temperature overnight. After 0.5N hydrochloric acid was added, andthe solution was extracted twice using chloroform (100 mL). Theresulting organic layer was washed with a saturated brine, and driedover anhydrous magnesium sulfate, and the solvent was distilled off.Further recrystallization from IPE afforded 276 mg of white crystals.

¹H-NMR (CDCl₃) δ1.96 (3H, s), 3.61 (1H, d, J=18.2 Hz), 4.44 (1H, d,J=18.2 Hz), 7.39-7.62 (8H, m), 7.75 (1H, dd, J=7.1, 1.1 Hz), 7.90 (1H,d, J=7.6 Hz), 8.06 (1H, d, J=8.1 Hz), 8.45 (1H, d, J=8.1 Hz).

¹³C-NMR (CDCl₃) δ21.0, 41.6, 67.4, 124.4, 124.7, 126.0, 126.8, 128.5,128.8, 129.2, 129.5, 129.6, 130.1, 130.7, 133.7, 134.4, 135.7, 152.9,165.7, 171.5, 171.9.

EXAMPLE 17 5,5-Dimethyl-3-(2-naphthylsulfonyl)imidazolidine-2,4-dione(Compound 17)

1.28 g of 5,5-dimethylimidazolidine-2,4-dione was dissolved intetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,2-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and themixture was stirred at room temperature overnight. After the solvent wasdistilled off, ethyl acetate (150 mL) was added to the reactionsolution, and washed with 1N hydrochloric acid, an aqueous saturatedsodium bicarbonate solution and a saturated brine in turn. The solutionwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded white crystals. The resultingfraction was recrystallized from IPE to obtain 232 mg of white crystals.

¹H-NMR (CDCl₃) δ1.41 (6H, s), 6.01 (1H, brs), 7.62-7.73 (2H, m),7.92-8.09 (4H, m), 8.73 (1H, s).

¹³C-NMR (CDCl₃) δ25.2, 59.0, 122.3, 127.9, 128.0, 129.7, 129.8, 130.0,130.8, 131.9, 134.6, 135.8, 150.4, 172.3.

EXAMPLE 18 5,5-Dimethyl-3-naphthylsulfonyl imidazolidine-2,4-dione(Compound 18)

5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved intetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,1-naphthalene sulfonyl chloride (2.38 g) was added at 0° C., and themixture was stirred at room temperature overnight. After the solvent wasdistilled off, 150 mL of ethyl acetate was added to the reactionsolution, and the solution was washed with 1N hydrochloric acid, anaqueous saturated sodium bicarbonate solution and a saturated brine inturn. The solution was dried over anhydrous magnesium sulfate, and thesolvent was distilled off. Further purification by silica gelchromatography (hexane:ethyl acetate=2:1) afforded 369 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.34 (6H, s), 6.24 (1H, brs), 7.58-7.72 (3H, m), 7.97(2H, d, J=7.6 Hz), 8.17 (2H, d, J=8.1 Hz), 8.53 (1H, dd, J=8.4, 1.2 Hz),8.70 (1H, d, J=8.1 Hz).

¹³C-NMR (CDCl₃) δ25.1, 59.0, 123.2, 124.1, 127.3, 128.4, 129.3, 129.4,132.3, 133.0, 134.0, 136.5, 150.6, 172.7.

EXAMPLE 19 5-Methyl-3-(2-naphthylsulfonyl)-5-phenylimidazolidine-2,4-dione (Compound 19)

5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) wassuspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride(1.02 g) was added slowly, and the mixture was stirred at roomtemperature overnight. After the solvent was distilled off, ethylacetate (100 mL) was added to the reaction solution, and the solutionwas washed with 1N hydrochloric acid, an aqueous saturated sodiumbicarbonate solution and a saturated brine in turn. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.

¹H-NMR (CDCl₃) δ1.74 (3H, s), 7.30-7.41 (6H, m), 7.63-7.74 (2H, m),7.92-8.05 (4H, m), 8.71 (1H, brs).

¹³C-NMR (CDCl₃) δ25.4, 63.6, 122.3, 125.2, 128.0, 128.0, 128.8, 129.0,129.8, 129.9, 130.0, 130.8, 131.9, 134.6, 135.9, 137.8, 151.0, 171.0.

EXAMPLE 20 1-Benzyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (Compound 20)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (200 mg) wasdissolved in DMF (2 mL), benzyl bromide (45 mg) was added, and potassiumcarbonate (36 mg) was further added. The reaction solution was stirredat room temperature overnight. Ethyl acetate (100 mL) was added to thereaction solution, and the solution was washed with 1N hydrochloricacid, an aqueous saturated sodium bicarbonate solution and a saturatedbrine in turn. After the solution was dried over anhydrous magnesiumsulfate, and the solvent was distilled off. The resulting residue wasrecrystallized from IPE to obtain 55 mg of white crystals.

¹H-NMR (CDCl₃) δ4.58 (2H, s), 6.75 (1H, d, J=7.6 Hz), 6.99-7.10 (3H, m),7.33-7.45 (11H, m), 7.52-7.55 (2H, m), 7.62 (1H, d, J=7.3 Hz), 7.87-7.90(1H, m), 8.04 (1H, d, J=7.9 Hz), 8.38-8.41 (1H, m).

¹³C-NMR (CDCl₃) δ45.6, 75.5, 124.4, 124.6, 126.7, 127.2, 128.1, 128.2,128.4, 128.8, 128.8, 128.9, 129.3, 129.9, 129.9, 130.7, 133.7, 134.3,135.9, 136.2, 152.9, 166.0, 171.2.

EXAMPLE 213-Naphthylcarbonyl-1-(2-oxo-2-phenylethyl)-5,5-diphenylimidazolidine-2,4-dione (Compound 21)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) wasdissolved in DMF (2 mL), 2-bromoacetophenone (52 mg) was added, andpotassium carbonate (36 mg) was further added. The reaction solution wasstirred at room temperature overnight. Ethyl acetate (100 mL) was addedto the reaction solution, and the solution was washed with 1Nhydrochloric acid, an aqueous saturated sodium bicarbonate solution anda saturated brine in turn. After the solution was dried over anhydrousmagnesium sulfate, the solvent was distilled off. The resulting residuewas recrystallized from IPE to obtain 69 mg of white crystals.

¹H-NMR (CDCl₃+CD₃OD) δ4.79 (2H, s), 7.26-7.42 (12H, m), 7.48-7.64 (6H,m), 7.90 (2H, dt, J=7.2, 1.2 Hz), 8.08 (1H, d, J=8.2 Hz), 8.50 (1H, dd,J=8.8, 1.3 Hz).

¹³C-NMR (CDCl₃+CD₃OD) δ47.2, 75.1, 124.5, 124.9, 126.8, 127.5, 128.5,128.6, 128.7, 128.9, 129.3, 129.8, 130.2, 130.8, 133.5, 133.7, 134.3,136.4, 152.9, 165.8, 176.0, 190.0.

EXAMPLE 221-Methyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione(Compound 22)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (100 mg) wasdissolved in DMF (4 mL), and sodium hydride (60%, in oil) (10 mg) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes, methyliodide (37 mg) was added at 0° C., and the mixture was stirred at roomtemperature overnight. Water (100 mL) was added to the reactionsolution, and separated out white precipitates were filtered. Furtherrecrystallization using hexane:ethyl acetate=1:1 afforded 64 mg of whitecrystals.

¹H-NMR (CDCl₃) δ2.83 (3H, s), 7.34-7.41 (5H, m), 7.43-7.49 (6H, m),7.52-7.61 (2H, m), 7.69 (1H, dd, J=8.3, 1.2 Hz), 7.89-7.92 (1H, m), 8.06(1H, d, J=8.2 Hz), 8.42-8.45 (1H, m).

¹³C-NMR (CDCl₃) δ26.9, 74.6, 124.4, 124.7, 126.8, 128.4, 128.4, 128.8,129.0, 129.3, 129.8, 130.0, 130.7, 133.7, 134.2, 135.9, 152.5, 166.0,171.1.

EXAMPLE 23 1-Isobutyl-3-naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (Compound 23)

3-Naphthylcarbonyl-5,5-diphenylimidazolidine-2,4-dione (51 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, methylisobutyl iodide (23 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of whitecrystals.

¹H-NMR (CDCl₃) δ0.55 (6H, d, J=6.7 Hz), 0.92-1.02 (1H, m), 3.25 (2H, d,J=7.6 Hz), 7.26-7.61 (14H, m), 7.88 (1H, dd, J=6.1, 3.4 Hz), 8.02 (1H,d, J=8.4 Hz), 8.38 (1H, dd, J=6.2, 3.7 Hz).

¹³C-NMR (CDCl₃) δ20.0, 27.4, 49.3, 75.4, 124.4, 124.7, 126.7, 126.8,128.3, 128.6, 128.7, 128.8, 129.0, 129.0, 129.4, 129.7, 133.7, 134.1,136.8, 152.8, 166.1, 171.1.

EXAMPLE 241-(4-Fluorobenzyl)-5-methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (Compound 24)

5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 4-fluorobenzyl bromide (24 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 38 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.72 (3H, s), 3.91 (1H, d, J=15.4 Hz), 4.91 (1H, d,J=15.4 Hz), 6.92-7.00 (2H, m), 7.17-7.21 (2H, m), 7.32-7.62 (8H, m),7.72 (1H, dd, J=7.3, 1.2 Hz), 7.89 (1H, dd, J=6.8, 1.8 Hz), 8.05 (1H, d,J=8.2 Hz), 8.47 (1H, dd, J=7.5, 1.2 Hz).

¹³C-NMR (CDCl₃) δ21.7, 43.8, 67.6, 115.4, 115.7, 124.4, 124.6, 126.2,126.8, 128.5, 128.8, 129.2, 129.3, 129.8, 130.1, 130.2, 130.7, 132.6,132.7, 133.7, 134.3, 135.8, 153.1, 160.7, 164.0, 166.1, 171.8.

EXAMPLE 251-(3-Chlorobenzyl)-5-methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione(Compound 25)

5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine -2,4-dione (43 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 26 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.74 (3H, s), 3.90 (1H, d, J=15.6 Hz), 4.91 (1H, d,J=15.6 Hz), 7.11-7.28 (4H, m), 7.34-7.64 (8H, m), 7.74 (1H, dd, J=7.3,1.2 Hz), 7.91 (1H, d, J=7.4 Hz), 8.07 (1H, d, J=8.2 Hz), 8.46 (1H, d,J=8.4 Hz).

¹³C-NMR (CDCl₃) δ21.7, 43.9, 67.6, 124.4, 124.6, 126.2, 126.5, 126.8,128.1, 128.3, 128.5, 128.8, 129.2, 129.4, 129.5, 129.9, 130.0, 130.7,133.7, 134.3, 134.5, 135.7, 138.8, 153.1, 166.0, 171.8.

EXAMPLE 265-Methyl-3-naphthylcarbonyl-1-(2-oxo-2-phenylethyl)-5-phenylimidazolidine-2,4-dione(Compound 26)

5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (43 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 25 mg of 2-bromoacetophenone was added, and the mixture wasstirred at room temperature overnight. Ethyl acetate (9.5 mL) was addedto the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 33 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.94 (3H, s), 4.20 (1H, d, J=18.0 Hz), 5.13 (1H, d,J=18.0 Hz), 7.39-7.65 (11H, m), 7.84-7.91 (4H, m), 8.06 (1H, d, J=8.2Hz), 8.49 (1H, d, J=8.4 Hz).

¹³C-NMR (CDCl₃) δ21.1, 46.9, 67.5, 124.5, 124.8, 126.2, 126.7, 128.0,128.5, 128.7, 128.9, 129.4, 129.5, 129.8, 130.0, 130.8, 133.7, 134.1,134.2, 134.4, 136.4, 152.9, 165.8, 171.9, 191.7.

EXAMPLE 274-(5,5-Dimethyl-3-naphthylcarbonyl-2,4-dioxoimidazolidinylmethyl)benzonitrile(Compound 27)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine -2,4-dione (35 mg) wasdissolved in DMF (0.4 mL) and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 4-cyanobenzyl bromide (25 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 24 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.92 (6H, s), 4.60 (2H, s), 7.34 (2H, dt, J=8.2, 1.7Hz), 7.42-7.54 (5H, m), 7.56 (2H, dt, J=8.1, 1.7 Hz), 7.76 (1H, dd,J=7.3, 1.5 Hz), 7.88-8.00 (2H, m).

¹³C-NMR (CDCl₃) δ22.7, 42.1, 64.3, 123.5, 124.7, 124.7, 126.4, 127.3,128.7, 128.8, 129.2, 129.6, 130.6, 130.8, 132.6, 133.2, 133.4, 140.0,151.9, 168.2, 174.8.

EXAMPLE 281-(3-Chlorobenzyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione(Compound 28)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 3-chlorobenzyl bromide (26 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 14 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.92 (6H, s), 4.54 (2H, s), 7.14 (1H, dt, J=7.1, 1.7Hz), 7.19 (1H, dd, J=7.6, 0.6 Hz), 7.23-7.27 (2H, m), 7.44-7.55 (4H, m),7.76-7.80 (1H, m), 7.89-7.93 (1H, m), 7.98 (1H, dd, J=8.0, 0.5 Hz).

¹³C-NMR (CDCl₃) δ22.7, 42.1, 64.2, 123.5, 124.7, 124.8, 126.4, 126.6,127.4, 128.5, 128.5, 128.8, 129.7, 130.1, 130.8, 133.3, 133.6, 134.6,136.9, 152.0, 168.3, 174.8.

EXAMPLE 291-(4-Chlorobenzyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione(Compound 29)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 4-chlorobenzyl bromide (26 mg) was added, and the mixturewas stirred at room temperature overnight. Ethyl acetate (9.5 mL) wasadded to the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 20 mg of whitecrystals.

¹H-NMR (CDCl₃) δ1.90 (6H, s), 4.53 (2H, s), 7.18-7.26 (4H, m), 7.42-7.55(4H, m), 7.76 (1H, dd, J=8.1, 0.8 Hz), 7.90 (1H, d, J=7.8 Hz), 7.97 (1H,d, J=8.1 Hz).

¹³C-NMR (CDCl₃) δ22.7, 42.0, 64.2, 123.6, 124.7, 124.8, 126.4, 127.3,128.8, 129.0, 129.6, 130.1, 130.7, 133.2, 133.6, 133.7, 134.3, 152.0,168.3, 174.8.

EXAMPLE 305,5-Dimethyl-3-naphthylcarbonyl-1-(2-oxo-2-phenylethyl)imidazolidine-2,4-dione(Compound 30)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 2-bromoacetophenone (25 mg) was added, and the mixture wasstirred at room temperature overnight. Ethyl acetate (9.5 mL) was addedto the reaction solution, separated out white precipitates werefiltered, and the filtrate was concentrated and purified by silica gelchromatography (hexane:ethyl acetate=2:1) to obtain 7 mg of whitecrystals.

¹H-NMR (CDCl₃) δ2.04 (6H, s), 4.84 (2H, s), 7.42-7.61 (7H, m), 7.83-7.95(5H, m).

¹³C-NMR (CDCl₃) δ22.7, 44.8, 64.8, 123.8, 124.7, 124.7, 126.4, 127.4,128.0, 128.6, 128.9, 129.6, 130.6, 133.2, 133.6, 133.9, 134.2, 152.2,168.4, 175.2, 189.7.

EXAMPLE 315,5-Dimethyl-3-naphthylcarbonyl-1-(2-oxo-2-p-tolylethyl)imidazolidine-2,4-dione(Compound 31)

5,5-Dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 2-bromo-4-methylacetophenone (27 mg) was added, and themixture was stirred at room temperature overnight. Ethyl acetate (9.5mL) was added to the reaction solution, separated out white precipitateswere filtered, and the filtrate was concentrated and purified by silicagel chromatography (hexane:ethyl acetate=2:1) to obtain 12 mg of whitecrystals.

¹H-NMR (CDCl₃) δ2.04 (6H, s), 2.39 (3H, s), 4.81 (2H, s), 7.23 (2H, dd,J=8.6, 0.7 Hz), 7.46-7.55 (3H, m), 7.56 (1H, dd, J==7.8, 1.5 Hz), 7.74(2H, dt, J=8.2, 1.8 Hz), 7.84-7.95 (3H, m).

¹³C-NMR (CDCl₃) δ21.8, 22.8, 44.7, 64.7, 123.8, 124.7, 124.7, 126.4,127.4, 128.1, 128.6, 129.6, 129.6, 130.6, 131.5, 133.2, 133.7, 145.3,152.2, 168.4, 175.2, 189.2.

EXAMPLE 321-(2-(4-Methoxyphenyl)-2-oxoethyl)-5,5-dimethyl-3-naphthylcarbonylimidazolidine-2,4-dione(Compound 32)

5,5-Diemthyl-3-naphthylcarbonylimidazolidine-2,4-dione (35 mg) wasdissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) wasadded. Then, 30 mg of 2-bromo-4-methoxyacetophenone was added, and themixture was stirred at room temperature overnight. Ethyl acetate was(9.5 mL) was added to the reaction solution, separated out whiteprecipitates were filtered, and the filtrate was concentrated andpurified by silica gel chromatography (hexane:ethyl acetate=2:1) toobtain 11 mg of white crystals.

¹H-NMR (CDCl₃) δ2.04 (6H, s), 3.85 (3H, s), 4.79 (2H, s), 6.90 (2H, dt,J=8.9, 2.0 Hz), 7.46-7.58 (4H, m), 7.80-7.95 (5H, m).

¹³C-NMR (CDCl₃) δ22.8, 44.5, 55.5, 64.7, 114.1, 123.8, 124.7, 124.7,126.3, 127.0, 127.4, 128.6, 129.7, 130.3, 130.6, 133.2, 133.7, 152.3,164.3, 168.4, 175.3, 188.0.

EXAMPLE 33 5,5-Dimethyl-1,3-bisnaphthylcarbonyl imidazolidine-2,4-dione(Compound 33)

5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved intetrahydrofuran (50 mL), and sodium hydride (60%, in oil) (0.80 g) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,1-naphthoyl chloride (3.80 g) was added at 0° C., and the mixture wasstirred at room temperature overnight. Ethyl acetate (200 mL) was addedto the reaction solution, the mixture was washed with a saturated brine,and dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded 1.19 g of white crystals.

¹H-NMR (CDCl₃) δ2.06 (6H, s), 7.41-7.65 (7H, m), 7.72 (1H, dd, J=7.3,1.1 Hz), 7.84-7.92 (4H, m), 8.04 (1H, d, J=8.2 Hz), 8.54 (1H, d, J=8.5,0.8 Hz).

¹³C-NMR (CDCl₃) δ23.1, 64.4, 123.69, 124.5, 124.6, 124.7, 125.0, 126.4,127.0, 127.4, 128.3, 128.8, 128.8, 129.0, 129.6, 130.9, 130.9, 131.1,133.0, 133.3, 133.8, 135.5, 149.4, 164.8, 168.6, 172.7.

EXAMPLE 34 3-Naphthylcarbonyl-1,3-diazaspiro[4.5]decane-2,4-dione(Compound 34)

5,5-Pentamethylenehydantoin (2.00 g) was dissolved in tetrahydrofuran(10 mL), and sodium hydride (60%, in oil) (0.49 g) was added at 0° C.under ice-cooling. After stirred for 30 minutes, 1-naphthoyl chloride(2.33 g) was added at 0° C., and the mixture was stirred at roomtemperature overnight. After the solvent was distilled off, ethylacetate (100 mL) was added to the reaction solution, and the solutionwas washed with 1N hydrochloric acid, an aqueous saturated sodiumbicarbonate solution and a saturated brine in turn. After drying overanhydrous magnesium sulfate, the solvent was distilled off to obtain thewhite solid. Further recrystallization with IPE and ethyl acetateafforded 1.87 g of white crystals.

¹H-NMR (CDCl₃) δ1.24-1.35 (3H, m), 1.55-1.93 (7H, m), 7.00 (1H, brs),7.47-7.65 (3H, m), 7.72 (1H, dd, J=7.3, 1.2 Hz), 7.91 (1H, dd, J=8.8,1.7 Hz), 8.06 (1H, d, J=8.2 Hz), 8.43-8.47 (1H, m).

¹³C-NMR (CDCl₃) δ21.4, 24.3, 33.7, 61.8, 124.3, 124.7, 126.8, 128.4,128.7, 129.6, 130.2, 130.7, 133.7, 134.0, 153.2, 166.3, 174.1.

EXAMPLE 355,5-Dimethyl-1,3-bis-(2-naphthylsulfonyl)imidazolidine-2,4-dione(Compound 35)

5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved intetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,2-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and themixture was stirred at room temperature overnight. After the solvent wasdistilled off, ethyl acetate (150 mL) was added to the reactionsolution, and the solution was washed with 1N hydrochloric acid, anaqueous saturated sodium bicarbonate solution and a saturated brine inturn. After drying over anhydrous magnesium sulfate, the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded 597 mg of white crystals.

¹H-NMR (CDCl₃) δ1.81 (6H, s), 7.62-7.75 (4H, m), 7.91-8.04 (8H, m), 8.68(1H, s), 8.69 (1H, s).

¹³C-NMR (CDCl₃) δ25.2, 59.0, 122.2, 122.6, 127.9, 127.9, 128.0, 128.1,129.5, 129.9, 129.9, 130.0, 130.3, 131.4, 131.6, 131.8, 133.6, 134.5,135.7, 136.0, 150.4, 172.3.

EXAMPLE 36 5,5-Dimethyl-1,3-bisnaphthylsulfonyl imidazolidine -2,4-dione(Compound 36)

5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved intetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) wasadded at 0° C. under ice-cooling. After stirred for 30 minutes,1-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and themixture was stirred at room temperature overnight. After the solvent wasdistilled off, ethyl acetate (150 mL) was added to the reactionsolution, and the mixture was washed with 1N hydrochloric acid, anaqueous saturated sodium bicarbonate solution and a saturated brine inturn. After drying over anhydrous magnesium sulfate, the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded 160 mg of white crystals.

¹H-NMR (CDCl₃) δ1.78 (6H, s), 7.46-7.64 (6H, m), 7.92-7.99 (2H, m), 8.15(2H, t, J=8.5 Hz), 8.41-8.50 (3H, m), 8.59-8.64 (1H, m).

¹³C-NMR (CDCl₃) δ24.4, 66.8, 122.8, 123.3, 124.1, 124.3, 127.1, 127.4,128.1, 128.2, 128.7, 129.4, 129.5, 129.5, 131.4, 132.7, 133.5, 133.8,133.9, 134.0, 136.6, 137.0, 147.2, 170.2.

EXAMPLE 375-Methyl-1,3-bis-(2-naphthylsulfonyl)-5-phenylimidazolidine-2,4-dione(Compound 37)

5-Methyl-5-phenylimidazolidine-2,4-dione potassium salt (1.00 g) wassuspended in tetrahydrofuran (10 mL), 2-naphthalenesulfonyl chloride(1.02 g) was added slowly, and the mixture was stirred at roomtemperature overnight. After the solvent was distilled off, ethylacetate (100 mL) was added to the reaction solution, and the mixture waswashed with 1N hydrochloric acid, an aqueous saturated sodiumbicarbonate solution and a saturated brine in turn. The organic layerwas dried over anhydrous magnesium sulfate, and the solvent wasdistilled off. Further purification by silica gel chromatography(hexane:ethyl acetate=2:1) afforded 242 mg of white crystals.

¹H-NMR (CDCl₃) δ2.25 (3H, s), 7.12-7.26 (4H, m), 7.36 (1H, t, J=7.5 Hz),7.57-7.75 (5H, m), 7.81-8.02 (7H, m), 8.11 (1H, d, J=1.5 Hz), 8.69 (1H,d, J=0.6 Hz).

¹³C-NMR (CDCl₃) δ21.9, 70.1, 122.2, 123.0, 126.3, 127.7, 127.9, 128.0,128.1, 129.0, 129.1, 129.5, 129.9, 129.9, 130.0, 130.0, 130.3, 131.3,131.4, 131.6, 131.8, 133.6, 134.4, 135.2, 135.6, 136.0, 147.4, 168.2.

Experiment 1 Chymase and Tryptase Inhibition Activity

Experimental Method

The chymase inhibition activity was measured according to the method ofKato et al. (J. Biochem., Vol.103, pp820(1988)). That is, 72.5 μL of asolution adjusted so that the enzyme activity of recombinant humanchymase (JP-A No.10-87567) became 2.3 μUnit with HEPES buffer, was addedto 2.5 μL of a test substance dissolved in dimethyl sulfoxide (DMSO), atemperature was retained at 30° C. for 5 minutes, and 125 μL of 0.6 mMSuc-Ala-Ala-Pro-Phe-MCA (manufactured by Peptide Institute Inc.)/Trisbuffer as a substrate was added to obtain a reaction solution. Thereaction solution was set at a multi-well plate reader CYTOFLUOR Series4000 (manufactured by Perceptive Biosystems), and a change in thefluorescent intensity was measured at 30° C. for 30 minutes with time(excitation wavelength 360 nm, detection wavelength 450 nm).

As a control, 2.5 μL of DMSO containing no test substance was used, andthis was treated and measured similarly. As a blank, a Tris hydrochloricacid buffer was added instead of a chymase solution, and treated andmeasured similarly.

The chymase inhibition rate (%) was obtained by calculating a slope (S)of an approximation straight line for each test substance, a slope (C)of an approximation straight line for a control, a slope (Bs) of anapproximation straight line for a blank of each test substance, and aslope (Bc) of approximation straight line for a blank of a control froma change in the fluorescent intensity, and calculating from thefollowing equation.Inhibition rate (%)=[1−(S−Bs)/(C−Bc)]×100

Then, the tryptase inhibition activity was measured according to themethod of Muramatsu et al. (Biol. Chem. Hoppe-Seyler, vol.369,pp617(1988)). That is, 62.5 μL of a solution adjusted so that the enzymeactivity of human lung tryptase (manufactured by Sigma) became 7.9 μUnitwith 0.1M phosphate buffer-1.5M NaCl (pH7.1), was added to 2.5 μL of atest substance dissolved in DMSO, a temperature was retained at 30° C.for 5 minutes, and 125 μL of 0.6mM Boc-Val-Pro-Arg-MCA. HCl(manufactured by BACHEM)/0.1M phosphate buffer (pH7.1) as a substratewas added to obtain a reaction solution. The reaction solution was setat a multi-well plate reader CYTOFLUOR Series 4000 (manufactured byPerceptive Biosystems), and a change in the fluorescent intensity wasmeasured at 30° C. for 30 minutes with time (excitation wavelength 360nm, detection wavelength 450 nm). As a control, 2.5 μL of DMSOcontaining no test substance was used, and treated and measuredsimilarly. As a blank, 0.1M phosphate buffer-1.5M NaCl (pH7.1) was addedin place of a tryptase solution, and treated and measured similarly.

A tryptase inhibition rate (%) was obtained by calculating a slope (S)of an approximation straight line for each test material, a slope (C) ofan approximation straight line for a control, a slope (Bs) of anapproximation straight line for a blank of each test substance, and aslope (Bc) of an approximation straight line for a blank of a controlfrom a change in the fluorescent intensity, and calculating from thefollowing equation.Inhibition rate (%)=[1−(S−Bs)/(C−Bc)]×100Experimental Results

Regarding the compounds of the present invention, each 50% inhibitionconcentration (IC₅₀) was calculated from the chymase and tryptaseinhibition activity obtained by the aforementioned method. The resultsare shown in Table 1. These results demonstrate that the compoundsrepresented by the general formula (I) of the present invention have thechymase and/or tryptase inhibition activity.

TABLE 1 Human chymase and tryptase inhibition activity Test substanceChymase IC₅₀ Tryptase IC₅₀ Compound 1 6.6 × 10⁻⁸ M 3.9 × 10⁻⁷ M Compound2 3.4 × 10⁻⁷ M 4.6 × 10⁻⁸ M Compound 3 1.0 × 10⁻⁶ M 9.3 × 10⁻⁷ MCompound 5 1.2 × 10⁻⁶ M 9.7 × 10⁻⁷ M Compound 7 6.5 × 10⁻⁶ M 3.7 × 10⁻⁷M Compound 8 3.0 × 10⁻⁵ M 3.2 × 10⁻⁶ M Compound 9 7.3 × 10⁻⁷ M 1.0 ×10⁻⁶ M Compound 13 2.7 × 10⁻⁶ M 1.6 × 10⁻⁶ M Compound 14 2.6 × 10⁻⁷ M1.6 × 10⁻⁶ M Compound 16 9.1 × 10⁻⁷ M 1.8 × 10⁻⁶ M Compound 22 3.5 ×10⁻⁶ M 8.9 × 10⁻⁸ M Compound 23 2.8 × 10⁻⁷ M 4.4 × 10⁻⁶ M Compound 255.8 × 10⁻⁷ M 8.6 × 10⁻⁵ M Compound 27 5.4 × 10⁻⁷ M 7.1 × 10⁻⁶ M Compound28 2.2 × 10⁻⁶ M 2.2 × 10⁻⁶ M Compound 30 3.3 × 10⁻⁶ M 7.2 × 10⁻⁶ MCompound 33 1.8 × 10⁻⁶ M 1.5 × 10⁻⁶ M Compound 34 3.2 × 10⁻⁵ M 2.8 ×10⁻⁷ M

Experiment 2 Rat Mast Cell Histamine Release Inhibition Test

Experimental Method

A rat was killed by exsanguinations under ether anesthesia, and 30 mL ofa buffer for mast cells (150 mM NaCl, 3.7 mM KCl, 3.0 mM Na₂HPO₄, 1 mMCaCl₂, 5.6 mM glucose) was injected intraperitoneally. An abdominal partwas massaged for 90 seconds, and a suspension of intraperitoneal cellwas taken. A suspension of an intraperitoneal cell collected from 5animals was centrifuged at 100 G at 4° C. for 5 minutes, a buffer formast cells was added, washed three times and, finally, adjusted so thatthe number of mast cells became 3 to 5×10⁵ cells/mL (hereinafter, thissolution is abbreviated as PEC).

Compound 5 was dissolved in DMSO to prepare a test drug solution at eachconcentration (final DMSO concentration 0.8%). 100 μL of the test drugsolution was added to 400 μL of the prepared PEC, and pre-incubated at37° C. for 15 minutes. After pre-incubation, each 50 μL of a solution ofphosphatidylserine (10 μg/ml) and concanavalin A(15 μg/ml) which is ahistamine-releasing substance was added, and further incubated for 20minutes. 1.4 mL of an ice-cooled buffer for mast cells was added to stopthe reaction, and centrifuged at 250 G at 4° C. for 10 minutes. Anamount of the histamine supernatant was quantitated using a fluorescentmethod. That is, 20 μL of 1N NaOH was added to 40 μL of the supernatant,20 μL of a 1% o-phthalaldehyde solution in methanol was further added,and allowed to stand at room temperature for 5 minutes. Thereafter, 20μL of 3N hydrochloric acid was added, and the fluorescent intensity wasmeasured at an excitation wavelength of 350 nm and a fluorescentwavelength of 450 nm to obtain an amount of histamine.

A histamine release inhibition rate (%) was calculated from thefollowing equation:Inhibition rate (%)=[1−(S−B)/(C−B)]×100

-   -   S: amount of histamine in the supernatant, C: amount of        histamine in control, B: amount of histamine in blank        Test Results

TABLE 2 Inhibition of release of histamine from mast cells Test drugconcentration (μM) Inhibition rate (%) 100 83 80 78 40 59 8 28

As shown in Table 2, Compound 5 inhibited release of histamineconcentration-dependently.

Preparation Example 1

Tablet Compound 1 50 mg Lactose 80 mg Starch 17 mg Magnesium stearate  3mg Crystalline cellulose 10 mg

The above ingredients for one tablet are molded by the conventionalmethod. This tablet may be coated with a sugar coating or a film (e.g.ethylcellulose etc.).

Preparation Example 2

Capsule Compound 2 75 mg Mannit 75 mg Starch 17 mg Calcium stearate  3mg

The above ingredients for one capsule are uniformly mixed, granulated,and filled into a hard capsule by the conventional method. This granuleto be filled may be coated with a sugar coating or a film (e.g.ethylcellulose etc.) as necessary.

Preparation Example 3

Aqueous suspension eye drop Compound 9 0.5 gHydroxypropylmethylcellulose 0.1 g Sodium chloride 0.9 g Sodiumdihydrogen phosphate dihydrate 0.1 g Benzalkonium chloride 0.005 g  0.1Nsodium hydroxide q.s. (pH7.2) Purified water Total 100 mL

Hydroxypropylmethylcellulose is dispersed in about 80 mL of purifiedwater by warming, and cooled to room temperature to dissolve it. To thissolution are added sodium chloride, sodium dihydrogen phosphatedihydrate and benzalkonium chloride to dissolve them, and 0.1N sodiumhydroxide is added to adjust to pH 7.2. To this solution is addedCompound 1, and suspended uniformly with a homogenizer. Purified wateris added to make a solution of total 100 mL, to prepare an aqueoussuspension for an eye drop.

Industrial Applicability

Since the compound represented by the general formula (I) of the presentinvention or a pharmaceutically acceptable salt has the excellentchymase and/or tryptase inhibition activity, it is useful as an agentfor preventing/treating various diseases associated with chymase and/ortryptase.

Some embodiments of the present invention have been explained in detailabove. However, a person skilled in the art can variously modify oralter the shown particular embodiments without substantially departingfrom the novel teaching and advantages of the present invention, andsuch modification and alteration are all included in the scope of thespirit of the present invention claimed in claims below.

The present application is based on Japanese Patent ApplicationNo.2001-112373 which was filed in Japan, the entire contents of whichare included in the present application.

1. A compound represented by the general formula (I):

wherein R¹ and R² are the same or different, and denote a lower alkylgroup or a phenyl group, or R¹ and R² are taken together to form a ring,R³ denotes an optionally substituted naphthyl group or heterocyclicgroup, A denotes oxygen or NR⁴ wherein R⁴ is hydrogen or optionallysubstituted lower alkyl group, or NB²R⁵ wherein R⁵ is aryl group, and B²is carbonyl group or sulfonyl group, and B¹ denotes a carbonyl group ora sulfonyl group, or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R¹ and R² are the same ordifferent, and are a lower alkyl group or a phenyl group, R³ is a furylgroup or an optionally substituted naphthyl group, and A is oxygen orNR⁴ wherein R⁴ is hydrogen or optionally substituted lower alkyl groupin the general formula (I), or the pharmaceutically acceptable saltthereof.
 3. The compound according to claim 1, wherein B¹ and B² are acarbonyl group in the general formula (I), or the pharmaceuticallyacceptable salt thereof.
 4. A medicament, which comprises the compoundas defined in claim 1, or a pharmaceutically acceptable salt thereof. 5.A chymase and/or tryptase inhibiting agent, which comprises the compoundas defined in claim 1, or a pharmaceutically acceptable salt thereof. 6.The medicament according to claim 4, which is an agent for treatingdiseases associated with chymase and/or tryptase.
 7. The medicamentaccording to claim 6, wherein the disease associated with chymase and/ortryptase is allergic, inflammatory or circulatory disease.
 8. Themedicament according to claim 6, wherein the disease associated withchymase is chorioretinopathy, glaucoma, myopia or asthenopia.
 9. Apharmaceutical composition, which comprises the compound as defined inclaim 1, or a pharmaceutically acceptable salt thereof.
 10. A method oftreating a disease associated with chymase and/or tryptase, whichcomprised administering an effective amount of the compound as definedin claim 1, or a pharmaceutically acceptable salt thereof to awarm-blooded animal, wherein the disease is selected from the groupconsisting of pancreatitis, ulcerative colitis, Crohn's disease,nephritis, hepatitis, bronchopneumonia, atopy, arthritis, rheumatism,keratoconjunctivitis, iridocyclitis, uveitis, orbital inflammation,vernal catarrh, allergic rhinitis, restenosis after circulatory disease,restenosis after blood vessel disorder due to percutaneous transluminalangioplasty, diabetic or non-diabetic renal disorder, peripheralcirculatory disorder, itching associated with inflammatory or allergicdisorder, chorioretinopathy, retinitis pigmentosa, macular degeneration,ischemic optic nerve disease, arteriovenous occulusion, diabeticretinopathy, choroidal disease following retinal lesion, glaucoma,myopia, asthenopia, thrombophlebitis, disseminated intravascularcoagulation, psoriasis, scleroderma, interstitial pneumonia, pulmonaryfibrosis, hepatic cirrhosis, periodontal disease and pterygium.
 11. Amethod for manufacturing a chymase and/or tryptase inhibiting agent,which comprised mixing the compound of claim 1 or a pharmaceuticallyacceptable salt thereof with an excipient, binder, disintegrating agent,lubricant, absorption promoter, buffer, surfactant, solubilizer,preservative, emulsifier, isotonic or pH adjusting agent.